The National Children's Study (NCS) is prospective longitudinal cohort study of the individual and combined effects of environmental exposures and gene environmental interactions on child health and development in a representative sample of approximately 100,000 children born in the United States. The children will be followed from before birth until age 21. The importance and timeliness of this study are based on many factors, including past experiences demonstrating profound effects of environmental exposures, such as exposures to alcohol during pregnancy and to lead in early childhood on child health and development; the special vulnerabilities of children to environmental exposures compared to adults; known ongoing exposures, such as prevalent levels of non-persistent pesticides or hours of media exposure per day in young children; and evidence for environmental contributions or causes to such high-impact conditions as autism, developmental delay and developmental disability, asthma, and obesity. The primary aim of the NCS is to investigate the separate and combined effects of environmental exposures (chemical, biological, physical, psychosocial) as well as gene-environment interactions on pregnancy outcomes, child health and development, and precursors of adult disease. Unique features of the study include its focus on environmental exposures at the earliest stages of pregnancy (as well as thereafter) and the breadth of planned exposure and outcome measurements. The NCS responds to the Congressional mandate of the Children's Health Act of 2000, that the NICHD and a consortium of federal agencies plan and conduct a longitudinal study of the impacts of environmental exposures on children. The NCS will employ a national probability sampling approach to select locations and participants for conduct of the study. The sampling design utilizes a multistage clustered approach. In the first stage, 105 locations (generally corresponding to single counties) were randomly selected from all U.S. counties. Seven of the locations serve as the initial or Vanguard Locations, participating in the pilot phase of the NCS. Because the focus of the study includes assessment of the impact of exposures that occur early in pregnancy, both pregnant women and their partners, and women of childbearing age, comprise the initial target population for enrollment. Data will be collected in combinations of face-to-face contacts and remote collection methods, e.g., telephone, computer, or mail-in questionnaires. The expected frequency of contact (face-to-face or remote) is approximately every three months through age one, every six months through age five years and annually thereafter. For a sample of children enrolled in the study, visits will also be made to child care and school settings for collection of environmental samples and observational data. Anticipated biologic specimens include blood, urine, hair, and nail clippings from mothers and children; blood, urine, and hair from fathers; cord blood, umbilical cord and placental tissues, and meconium collected at/around the time of delivery; vaginal swabs, and breast milk from mothers. Anticipated environmental samples include air, dust, soil, food, and water. The National Children's Study has initiated recruitment at 30 study locations around the United States. The Study is the largest long-term study of children's health ever conducted in the United States.